. The prinicipal aim of this research program is to explore a new approach to the design and synthesis of irreversible enzyme inhibitors. Initially the investigators plan to apply this new concept to irreversible inhibitors of HIV-1 protease. The central thesis of this program is the strategic attachment of an a-dicarbonyl unit to a potent reversible enzyme inhibitor such that it becomes an irresversible inhibitor. To achieve these design objectives the applicant plans to (1) identify an enzyme which has been shown by X-ray crystallography or other means to possess an arginine residue near the active site; (2) select an appropriate known, high affinity inhibitor of that enzyme; and then (3) attach a dicarbonyl containing substituent to the inhibitor in such a way as to allow the arginine side chain and dicarbonyl unit to approach within bonding distance without interfering with the recognition of the inhibitor by the enzyme.